L1 (Long Interspersed Nuclear Element 1) retrotransposons are the most active mobile elements in the human genome. They are present in over 500,000 copies. L1 insertions can disrupt gene function and add to the overall mass of the genome. Despite their abundance, very little is known about how Lls are regulated. In this proposal, I investigate three potential strategies used by mammalian cells to contain L1 damage to the genome: 1. Repair double stranded DNA breaks that are caused by or used for L1 insertions. 2. Kill cells with damaging L1 insertions by apoptosis. 3. Try to prevent L1 insertion by using RNA interference to destroy L1 RNA. To investigate these hypothesized modes of L1 regulation, my lab has developed a flow cytometric assay to monitor L1 retrotransposition in cultured cells. We have also created mice with green fluorescent protein tagged L1 transgenes. A better understanding of how L1 retrotransposition is regulated should yield important insights into L1 biology, mechanism and the potential of L1s to contribute to genomic instability in cancer.